Diltiazem-cis-(+)-3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2,3-dihydro-2-)4 -methoxyphenyl)-1,5-benzothiazepin-4(5H)-one hydrochloride, is a benzothiazine derivative which is a calcium ion influx inhibitor, i.e., a slow channel blocker or calcium antagonist. Diltiazem hydrochloride has a molecular weight of 450.98 and is a white to off-white crystalline powder, which is soluble in water, methanol, and chloroform.
Diltiazem hydrochloride has been shown to be useful in alleviating symptoms of chronic heart disease, particularly angina pectoris and myocardial ischemia, while displaying a low incidence of side effects. Diltiazem is conventionally administered orally as diltiazem hydrochloride.
Diltiazem is extensively metabolized by the liver and excreted by the kidneys and in bile. Although precise mechanisms of its anti-anginal actions are still being delineated, diltiazem is believed to act in the following ways. Diltiazem has been shown to produce increases in exercise tolerance, probably due to its ability to reduce myocardial oxygen demand. This is accomplished in reductions in heart rate and systemic blood pressure at submaximal and maximal exercise work loads. In animal models, diltiazem interferes with the slow inward (depolarizing) current in excitable tissue. It causes excitation-contraction uncoupling in various myocardial tissues without changes in the configuration of the action potential. Diltiazem produces relaxation of coronary vascular smooth muscle and dilation of both large and small coronary arteries at drug levels which cause little or no negative inotropic effect. The resultant increases in coronary blood flow (epicardial and subendocardial) occur in ischemic and non-ischemic models and are accompanied by dose-dependent decreases in systemic blood pressure and decreases in peripheral resistance.
Like other calcium antagonists, diltiazem decreases sinoatrial and atrioventricular conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In the intact animal, prolongation of the AH interval can be seen at higher doses.
In humans, diltiazem prevents spontaneous and ergonovine-provoked coronary artery spasm. It causes a decrease in peripheral vascular resistance and a modest fall in blood pressure, and in exercise tolerance studies in patients with ischemic heart disease, reduces the heart rate-blood pressure product for any given work load.
Diltiazem is absorbed from the tablet formulation to about 80% of a reference capsule and is subject to an extensive first-pass effect, giving an absolute bioavailability (compared to intravenous dosing) of about 40%.
Various types of sustained release diltiazem formulations have been described in the literature ("The Use of Diltiazem Hydrochloride in Cardiovascular Disorders", McAuley and Schroeder, Pharmacotherapy, Vol. 2, No. 3, p. 121, May/June 1982) and in the following United States patents, the disclosures of materials used (to the extent pertinent) and manufacturing techniques (to the extent properly disclosed) which are incorporated by reference herein: U.S. Pat. Nos. 5,002,776, 4,960,596, 4,917,899, 4,894,240, 4,891,230, and 4,721,619. However, all but one of these (4,960,596) involve the use of organic acid which may have an irritating effect.
Accordingly, a need exists for a sustained release diltiazem formulation for twice daily administration which does not have an irritating effect and which has a satisfactory dissolution rate or pattern.